A comparison of adverse event rates in a fixed-dose study comparing venlafaxine 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine use. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one venlafaxine group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value <= 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation.

Physical and Psychological Dependency

Main article: SSRI discontinuation syndrome Discontinuation of Venlafaxine

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.

Notwithstanding these in-vitro and non-human research findings, some patients using venlafaxine may become dependent on this drug. This is especially noted if a patient misses a dose, but can also occur when reduction of dosage is done with a doctor's care. This may result in experiencing withdrawal symptoms described as severe discontinuation syndrome. The high risk of withdrawal symptoms may reflect venlafaxine's short half-life. Missing even a single dose can induce discontinuation effects in some patients. Discontinuation is similar in nature to those of SSRIs such as Paroxetine (Paxil or Seroxat). Sudden discontinuation of venlafaxine has a high risk of causing potentially severe withdrawal symptoms. As reported in 2001 by Haddad PM in the journal Drug Safety, "another strategy to consider is switching to fluoxetine, which may suppress the discontinuation symptoms, but which has little tendency to cause such symptoms itself and then discontinuing that.

As the drug has direct impact on mood (i.e., anti-depressant), many users who have suffered the effects of attempted withdrawal from this drug define their dependency on the drug also as being addicted. Although many other drugs can cause withdrawal symptoms which are not associated with addiction or dependence, for example, anticonvulsants, beta-blockers, nitrates, diuretics, centrally acting antihypertensives, sympathomimetics, heparin, tamoxifen, dopaminergic agents, antipsychotics, and lithium, addiction or dependence is a more common effect described for drugs that (are thought to, or may) improve mental well-being.

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